The present invention relates to compounds capable of acting as androgen receptor antagonists, pharmaceutical formulations containing the same, and methods of use thereof.
The androgen receptor (AR) is a member of a large family of ligand-dependent transcriptional factors known as the steroid receptor superfamily. Chang et al., Proc. Natl. Acad. Sci. USA, 85, 7211-7215 (1988). Beato, M., Cell, 56, 335-344 (1989). Androgens and the AR play an important role in the growth of the normal prostate and prostate cancer. Prostate cancer represents the most common male malignancy in the United States. Landis et al., Cancer J. Clin., 48, 6-29 (1998). Recently, antiandrogens such as hydroxyflutamide (HF) in combination with surgical or medical castration have been widely used for the treatment of prostate cancer. Crawford et al., New Engl. J. Med., 321, 419-424 (1989). Several compounds, including cyprosterone, HF, and bicalutamide (shown below), have been used clinically in the treatment of prostate cancer. 
The synthetic steroidal antiandrogen cyprosterone is one of the first antiandrogens used clinically in Europe, McLeod, D., G., Cancer, 71, 1046-1049 (1993) but it has many side effects. Neumann et al., J. Clin. Oncol., 1, 41-65 (1982). HF and bicalutamide are both nonsteroidal antiandrogens. Bicalutamide is a newer nonsteroidal antiandrogen originally thought to have a pure antiandrogen activity without agonist activity. It has a longer half-life (6 days) and a higher binding affinity to the AR than HF. Verhelst et al., Clin. Endocrinol., 41, 525-530 (1994). (a) Kelly et al., J. Urol. (1993), 149, 607-609; (b) Scher et al., Prostate Cancer. J. Clin. Oncol., 11, 1566-1572 (1993).
Although antiandrogen hormone therapy has been widely used for the treatment for prostate cancer, some antiandrogens may act as AR agonists which may result in xe2x80x9cantiandrogen withdrawal syndrome.xe2x80x9d Miyamoto et al., Proc. Natl. Acad. Sci. USA, 95, 7379-7384 (1998). A currently accepted hypothesis postulates that mutations in androgen receptors may account for why HF, the active metabolite of flutamide, can activate androgen receptor target genes and stimulate prostate cancer growth. Miyamoto et al., Proc. Natl. Acad. Sci. USA, 95, 7379-7384 (1998). The same mechanism is used to explain the xe2x80x9cflutamide withdrawal syndrome,xe2x80x9d in which patients who experience an increase in prostate-specific antigen (PSA) while taking flutamide, have a decrease in PSA after withdrawal of treatment. Indeed, HF can activate androgen receptor target genes, such as PSA and MMTV-LTR (a reporter gene which expressed androgen-response element), in the presence of ARA70, the first identified androgen receptor co-activator. Yeh et al., The Lancet, 349, 852-853 (1997). Because this syndrome often leads to the failure of androgen-ablative therapy, it is desirable to develop better antiandrogens without agonist activity.
The phenolic diarylheptanoid curcumin (1) is the major pigment in turmeric. Curcumin and its analogs show potent anti-oxidant activity, anti-inflammatory activity, Nurfina et al., Eur. J. Med. Chem., 32, 321-328 (1997) cytotoxicity against tumor cells, Syu et al., J. Nat. Prod., 61, 1531-1534 (1998), antitumor-promoting activities, Sugiyama et al., Biochem. Pharmacol., 52, 519-525 (1996). Ruby et al., Cancer Lett., 94, 79-83 (1995) and antiangiogenesis activity (J. L. Arbiser et al. Mol. Med. 4: 376 (1998)).
Two cyclic diarylheptanoids, 13-oxomyricanol and myricanone, exhibiting potent antitumor promoting effects on DMBA-initiated and TPA-induced mouse skin carcinogenesis have been reported. Ishida et al., Cancer Lett., 159. 135-140 (2000). In the present study, a number of novel curcumin analogues have been prepared and evaluated for antagonistic activity against the AR in the presence of androgen receptor coactivator, ARA70, using two human prostate cancer cell lines, PC-3 and DU-145. PC-3 cells are androgen-independent tumor cells that do not express functional AR. DU-145 cells are androgen-independent tumor cells that also do not express functional AR.
According to embodiments of the present invention, the present invention relates to a compound according to formula I: 
wherein:
R1 and R2 are each independently selected from the group consisting of alkoxy, nitro, amino, and dialkylamino;
R3 and R4 are each independently selected from the group consisting of hydroxy, alkoxy, and xe2x80x94OR7C(O)R8, wherein R7 is lower alkylene and R8 is alkoxy;
or R1 and R3 together are alkylenedioxy;
or R2 and R4 together are alkylenedioxy;
R5 and R6 are each independently selected from the group consisting of H, halogen, and nitro;
X1 is N, or X1 is C bonded to a H, alkoxy or nitro; and
X2 is N, or X2 is C bonded to a H, alkoxy or nitro.
According to still other embodiments of the present invention, the present invention relates to a compound according to formula II: 
wherein:
R11 and R12 are each independently selected from the group consisting of alkoxy, nitro, amino, and dialkylamino;
R13 and R14 are each independently selected from the group consisting of hydroxy, alkoxy, and xe2x80x94OR18C(O)R19, wherein R18 is lower alkylene and R19 is alkoxy.
or R11 and R13 together are alkylenedioxy;
or R12 and R14 together are alkylenedioxy;
R15 and R16 are each independently selected from the group consisting of H, halogen, and nitro;
R17 is xe2x80x94R20C(O)OR21, wherein R20 is alkylene and R21 is H or alkyl;
X3 is N, or X3 is C bonded to a H, alkoxy or nitro; and
X4 is N, or X4 is C bonded to a H, alkoxy or nitro.
According to yet other embodiments of the present invention, the present invention relates to compounds according to the formula III: 
wherein:
R25 and R26 are each independently H or lower alkyl;
R27, R28, R29 and R30 are each alkoxy;
R31 is H or lower alkyl.
According to still other embodiments of the present invention, the present invention relates to a method of treating cancer, comprising administering to a subject in need thereof a treatment effective amount of a compound according to the formulas above. Examples of cancers that may be treated include, but are not limited to, skin cancer, small cell lung cancer, testicular cancer, lymphoma, leukemia, esophageal cancer, stomach cancer, colon cancer, breast cancer, endometrial cancer, ovarian cancer, central nervous system cancer, liver cancer and prostate cancer.
According to yet other embodiments of the present invention, the present invention relates to a method of inducing androgen receptor antagonist activity, the method comprising contacting a cancer cell with an androgen receptor antagonist effective amount of a compound according to the formulas above.
According to other embodiments of the present invention, the present invention relates to a method of inducing androgen receptor antagonist activity in a subject afflicted with an androgen-related affliction. Examples of androgen-related afflictions include, but are not limited to, baldness, hirsutism, behavioral disorders, acne, and uninhibited spermatogenesis wherein inhibition of spermatogenesis is so desired.